Migraine

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Introduction

Despite efforts made in 1962 and 1988 to better define the clinical parameters of migraine, concepts of the basic pathophysiologic mechanisms responsible for the disease have remained essentially unchanged until the last decade. Therapeutic efforts concentrated on countering the vasodilatory status of the cerebral circulation to which was attributed the clinical manifestations of migraine. During the past decade, however, it has become increasingly apparent that, while cerebral vasodilatation may be in large part responsible for migraine symptomatology, it may actually be the effect of the migrainous process rather than its basic etiologic mechanism.

It is now generally accepted that the migrainous process is primarily the result of an imbalance between neurotransmitters, specifically dopamine and serotonin, and that migraine is the consequence of lowered absolute or relative levels of serotonin. Remedial measures to correct this imbalance have resulted in the emergence of new therapeutic agents, which have had dramatic beneficial effects on the migraineur. The following Continuing Medical Education program will review the current thinking in regard to migraine with special emphasis on these new therapeutic modalities.

The Definition and Diagnosis of Migraine

In 1962, an ad hoc committee of the National Institutes of Health issued a classification of headaches including diagnostic criteria for migraine. Over the years, however, a number of problems developed concerning the classification, and in 1988, the criteria were revised by the International Headache Society (IHS). Migraine was divided into two major categories, primarily based on the presence or absence of an aura.

The IHS criteria for migraine without an aura (which constitutes about 80% of migraine attacks), included the following:

1. Headache lasting 4-72 hours, characterized by at least two of the following:

a. Unilateral pain

Throbbing pulsatile quality of the pain

c. Pain moderate to severe in intensity

d. Pain aggravated by routine activities

2. Headache lasting 4-72 hours, characterized by at least one of the following:

a. Nausea and/or vomiting

Photophobia and phonophobia

3. Diagnosis should include at least five previous attacks and no evidence of underlying diease.

The IHS criteria for migraine with an aura includes the following:

1. Headache follows attacks fulfilling at least three of the following:

At least one aura symptom develops gradually over more than four minutes or two or more symptoms occur in succession

c. No aura symptom lasts more than sixty minutes

d. Headache follows aura with a free interval less than sixty minutes (may also begin before or simultaneously with the aura).

Although the above-listed criteria are used as a baseline for the diagnosis of migraine, the following limitations apply:

1. The criteria for migraine pain lack specificity. Hemicranial pain occurs only in 50 to 60% of attacks and headaches of a throbbing pulsatile quality are present in only 50 to 75% of attacks. No timing of the pain is given in reference to the attack.

2. The IHS criteria are compatible with multiple headache diagnoses because of overlapping of symptomatology.

3. No mention is made of the role of the response to therapy in classifying and diagnosing migraine.

The Demographic, Clinical, and Socioeconomic Aspects of Migraine

Migraine is one of the most common disorders seen by the primary physician. It is estimated that approximately 6% of men and 18% of women in the United States are migraineurs (migraine victims). his probably represents only the tip of the iceberg. There is a marked variability in the spectrum of clinical manifestations of migraine, not only from patient to patient, but in the same patient as well. Furthermore, there is no clear-cut diagnostic test to establish the diagnosis. As a result, migraine is not easily diagnosed. In fact, epidemiological studies indicate that only 40% of women and 30% of men who fulfill the diagnostic criteria for migraine are ever so diagnosed. In the American Migraine Study, a total of 78% of men and 59% of women who were found to have migraine based on self-reported symptom data had ever been so diagnosed by a physician.

According to a new study by researchers at the Mayo Clinic, the incidence of migraine rose dramatically during the 1980s, 56% in women and 34% in men. The most striking increase occurred in women aged 20 to 29. The authors suggested that this trend may be the result of several factors, including “Changes in social environment during the 1980s [that] increased the stress imposed on young women and stress may be a major cause of the increase in migraine.”

They also attributed the increase to more frequent visits to physicians by migraineurs and better awareness of the diagnostic criteria by physicians.

In addition to the impact on the individual, migraine poses a serious public health impact. A recent data review by Hu et al reported that migraineurs required 3.8 bed rest days for men and 5.6 bed rest days for women per year, resulting in a total of 112 million bedridden days. Migraine costs employers about $13 billion a year because of missed workdays and impaired work function, of which close to $8 billion is directly due to missed workdays. Patients of both sexes, aged 30 to 49 years, incurred higher indirect costs compared to younger or older patients. Annual direct medical costs for migraine care were about $1 billion, with about $100 spent per diagnosed patient. Physician office visits accounted for about 60% of all costs. In contrast, emergency room visits contributed less than 1% of the direct costs. Less than 10% of migraine-related medical costs were borne by third-party payers, the burden falling primarily on the patients and their employers.

The Pathophysiology of Migraine

It has been recognized for years that vasodilatation of the cerebral vasculature is a distinguishing feature of migraine and of particular significance in the throbbing, pulsatile nature of the pain of migraine. Therapeutic intervention concentrated on this phenomenon, and it was regarded as the prime factor in the etiology of migraine. It has become increasingly apparent, especially over the last decade, that cerebral vasodilation, though significant in the production of the pain of migraine, is actually an effect of the migrainous process rather than its cause. Current thinking places the primary etiology as an imbalance of neurotransmitters, specifically dopamine and serotonin.

Serotonin, 5-hydroxy tryptamine, is one of over 30 different neurotransmitters that function in the human body. It is further divided into a number of subtypes. Those of the subtype 5HT1 are of particular relevance to migraine. Serotonin receptors exist throughout the body and are located not only in nerve tissue, but in the gastrointestinal tract and, most significantly, in the arterial walls of the cerebral (and probably other) circulations. Depending on which nerve pathways are activated and which of the many serotonin receptor sites are activated, serotonin has the capability of initiating a wide variety of responses. Generally speaking, serotonin exerts a calming effect, whereas dopamine is more excitatory in its actions. In addition to its effect on cerebral blood vessels, serotonin plays a role in mood, sleep function, sexual behavior, and other important functions. Serotonin levels in the brain, particularly those of the subtype 5HT1 , drop during an attack of migraine resulting in a clinical picture that in large measure is related both to depressed levels of serotonin as well as a relative dopamine over-activity. A significant component of the painful migrainous process is a loss of nervous control of the regulation of certain cerebral blood vessels, resulting in their dilatation and stretching, along with exudation into the surrounding tissues and meninges.

Risk Factors in the Development of Migraine

It is not completely understood why certain individuals are prone to developing migraine whereas others, under apparently similar circumstances, do not. Some predisposing factors, however, have been identified. The individual migraine threshold may be thought of as a complex interaction of genetics, with internal and external environmental factors.

1. Genetic Predisposition

Studies of migraine with aura have shown familial aggregation of the disorder which cannot be explained by simple mendelian inheritance. There are three generic loci for familial hemiplegic migraine, which is a rare subtype of migraine with aura, with autosomal dominant inheritance. A study of twins demonstrated that in monozygotic twins, in which one twin has migraine, the risk of the other developing migraine with aura is triple that of the risk in a similar situation in dizygotic twins. The presence of a migraine “generator” has been proposed as an additional genetic factor. Migraineurs appear to inherit a more “sensitive” nervous system, that is, one that is prone to react and overreact to changes in the internal or external environment.

2. Internally Derived Risk Factors

A number of factors have been identified, including the following:

a.) Hormonal fluctuations. The most noticeable of these is the fluctuation in estrogen that occurs during the menstrual cycle. Menstrual migraine occurs in 60% of female migraineurs and 14% suffer only at the time of menses. Estrogen itself does not produce migraine; in fact, migraine attacks are less frequent in states of high estrogen levels, such as pregnancy, and therapeutic efficacy in migraine has been attributed to estrogen implants. Instead, attacks seem to be provoked by rapid decreases in estrogen levels, a process which seems to sensitize the migraine threshold to internal and external environmental stimuli. The association of migraine with menstruation is supported by the fact that migraine is more prevalent in females than in males within accepted gender ratio of approximately 3:1.

b.) Diet and food additives. Additives are often implicated as triggering migraine attacks and the list of responsible agents is lengthy. Although about one-third to one-half of migraineurs say certain foods trigger their headaches, studies have been largely inconclusive, and most researchers believe the actual numbers of sufferers who respond to food triggers is small. Recently, for example, a study reported that chocolate one of the most often cited trigger foods to be an unlikely culprit.18 Other oft-cited food triggers include caffeine, red wine and alcohol, tannins and tyramine, ice cream, artificial sweeteners, monosodium glutamate (MSG), and other additives, such as nitrites and nitrates.

Of this lengthy list, caffeine appears to be a likely offender and both caffeine withdrawal or caffeine excess have been documented to precipitate a migraine attack. This is somewhat paradoxical in that caffeine is a frequent component of over-the-counter migraine analgesics, e.g, Excedrin. For many migraineurs, alcohol can provoke an attack, apparently by its serotonin-depleting action. Although tyramine may produce headaches under certain conditions, its role in the precipitation of migraine attacks is dubious. The phenol present in red wine appears to be a more important contributor than its tyramine content.

There is no substance that can trigger migraine universally in all sufferers; the problem appears to be specifically related to the individual. Even in individuals who claim that food triggers attacks, there may not be a 100% response at all times. Other factors such as hormonal changes and stress may be contributors. The issue is complicated by the fact that quantity of the ingestant may play a role and the responses may not result for several hours.

e.) Stress and emotional trauma. There is little doubt that stress or severe emotional trauma, such as loss, death, argument or fear, can trigger an attack of migraine and in many cases this is the most common precipitating factor.

3. Externally-derived risk factors

a.) Smoking. Nicotine appears to intensify the reactivity of the nervous system and may predispose one to a migraine attack.

The above list of potential risk factors for migraine attack illustrate the need for the migraineur to pursue as regulated a lifestyle as possible. The migraineur is born with a highly sensitive nervous system and migraine may occur when the individual attempts to adjust to an environment that overloads physiological mechanisms. This sensitive nervous system requires stability and routine. For example, he/she must establish regular meal times and consistent sleep and waking habits. Adoption of such a regulated lifestyle is an essential feature of the non-pharmacological management of migraine.

The Clinical Characteristics of Migraine

During the throes of an acute attack of migraine, the patient’s symptoms are often dramatic, but in most cases, there is a predictable train of events that occurs prior to and following the acute attack. Actually, migraine attack can be divided into five distinct phases, the definitions of which are extremely important, especially from the standpoint of migraine management. The recognition of these phases provides the patient with insight into the attack and an understanding of the therapy employed. The phases, from one to five, are: prodrome, aura, headache, resolution and postdrome.

Phase One: Prodrome

The prodrome of an acute migraine attack is composed of a constellation of signs and symptoms that serve to warn the patient of an impending attack. The prodrome is present in 50 to 80% of migraine attacks. The symptoms of the prodrome vary from patient to patient but are generally non-specific, consisting of alterations in mood that vary from depression to euphoria, irritability, changes in cognitive functions, and inability to concentrate. The patient may complain of generalized fatigue and drowsiness.

It is important for the patient to identify these phenomena so that treatment necessary to abort the migraine may be undertaken.

Phase Two: Aura

Although auras are popularized as typical manifestations of migraine, they actually occur in only about 15% of migraine attacks. The aura is distinct from the prodrome because it is regarded as a manifestation of a focal neurological disturbance. Most frequently the aura is visual in nature and consists of scintillation or flashing lights. Disturbances in vision may occur. Auras may be multiple and persist for hours. The usual individual aura lasts 15 to 45 minutes, and rarely more than an hour.

Auras may also be sensory in nature, usually manifested by numbness and tingling in various parts of the body with a superficial resemblance to the symptoms of a transient ischemic attack (TIA), although the sequence of appearance and disappearance of symptoms is opposite to that of a TIA. The aura is essentially a wave of neuronal depolarization producing a marching type of neurological phenomenon that disappears in the sequence that it arrived. In the case of TIAs, the first symptom representing the greatest deprivation of blood flow is the last to recede.

In addition to the more common visual and sensory types, auras can result in rather profound manifestations of losses in perception of time and space, and in basilar symptomatology of dysarthria, tinnitus, vertigo, incoordination, and loss of balance. Other rare examples of aura include hemiplegia and ophthalmoplegia.

The symptoms may mimic those of a more serious and lasting neurological abnormality and further investigation is warranted if a single aura persists more than 60 minutes or does not clear within the headache phase of the attack.

Phase Three: Headache

The headache phase is clearly the most dramatic, and interpreted by the inexperienced patient as the definitive migraine attack. As mentioned previously, the headache is attributable to the loss of cerebral vascular control with resultant cerebral vasodilatation and inflammatory sequelae in surrounding tissues.

The headache lasts from 4 to 72 hours, is unilateral, and is described as “throbbing” in approximately 60% of attacks. The pain is moderate to severe in intensity and increases with increased physical activity such as climbing stairs. In addition, there are usually accompanying systemic manifestations during the headache phase. Nausea is present in about 80% of cases and may progress to vomiting in 10 to 15%. Tenderness of the muscles of the scalp and neck is common. Sensory phenomena such as photophobia, phonophobia, and osmophobia may be present and cognition may be affected. The patient characteristically tends to withdraw from all exposures, frequently seeking the isolation of a dark, quiet room.

Phase Four: Resolution

During this phase, the chemical, neuroexcitatory, and sensory aberrations that were previously present return to normal. The precise mechanisms that spontaneously result in resolution are unknown. Often the process will revert with sleep or vomiting.

Phase Five: Postdrome

Following resolution of the headache, the patient is often left with a period of disability characterized by fatigue, anorexia, muscle soreness, and poor concentration. This phase may last up to two days.

The pattern of attacks varies from individual to individual. However, the attack usually follows a similar pattern in the individual migraineur. Once recognized, anticipation of this pattern aids the patient and physician in the use of appropriate therapy, both nonpharmacological and pharmacological.

Making the Diagnosis of Migraine

Although it is unusual for a migraineur to present with a completely classical clinical picture involving the five stages, enough of the pattern will be usually present to warrant the diagnosis. There are, however, a number of worrisome features that should alert the physician to the possibility of another diagnosis. These include the following:

1. Onset of headache after age 50

2. Onset of a new or different headache or the “worst ever experienced”

Migraine Prophylaxis

Nonpharmacological treatment, self-management, and OTC agents

Migraine is a cyclic phenomenon which has a tendency to become manifest during periods of relatively abrupt change, such as hormonal readjustments, environmental changes, and stressful life events. The patient can play a significant role in the prevention of migraine attacks by regulating his/her life style to prevent the occurrence of a triggering factor or, if it is not preventable, by coping and adjusting to it. Certain basic principles are helpful in this regard:

Consider biofeedback. Biofeedback is the process of bringing involuntary physiological functions under voluntary control, thereby training the nervous system to shut out unwanted stimulation. A number of techniques exist, but the use of audio tapes is probably most convenient; two 10-minute sessions daily is considered adequate. Monitoring of finger temperatures with a finger thermometer is a convenient way of assessing success. The normal fingertip temperature of 85oF is below 80oF as stress builds up and rises as biofeedback exerts a beneficial effect

There are several OTC agents that have been reported as helpful in the prophylaxis of migraine.

1. Riboflavin (vitamin B6) has been reported to decrease premenstrual syndrome symptoms and in a single, placebo-controlled study, was reported to have been significantly superior to placebo in the prevention of migraine attacks.

2. Magnesium is known to play an important role in smooth muscle relaxation and in the stimulation of nerve cells, possibly by playing a role in serotonin metabolism. Magnesium serum levels have been found to fluctuate during migraine attacks and the administration of 250 to 500mg of magnesium has been reported as beneficial in the prevention of migraine attacks and restoration of therapeutic responsiveness to serotonin agonists.

3. Feverfew (Tanacetum Partheniun) is a plant derivative reported to be beneficial in the prevention of migraine attacks.

4. Aspirin. In addition to its low-dose cardiovascular protective qualities, low dose aspiring has been reported as beneficial in the prevention of migraine headaches.

The Pharmacological Prophylaxis of Migraine

With the development of effective therapy of the acute migraine attack, the need for pharmacological prophylaxis has become less critical. Most clinicians feel that it is acceptable for a patient to experience four or five acute attacks a month provided that the attacks can be controlled. The National Headache Foundation stipulates that re-evaluation and probably prophylaxis are necessary when an individual requires acute treatment medications more than twice a week. Ultimately, it is the decision of the patient and the physician to determine when migraine control is inadequate and there is a need for prophylaxis.

Essentially, the following are criteria for the determination that migraine is not well controlled:

1. Medication being used too frequently.

Overuse of acute treatment should be avoided because it can worsen the underlying migraine and may lead to a pharmacologically-maintained headache, commonly referred to as analgesic rebound headache. Their frequent use may also lead to organ damage, especially to the kidneys, liver, and stomach.

The majority of chronic headache sufferers consume analgesics on a daily basis. Over a prolonged period this can result in a change in the character of the migraine pattern. While acute attacks still recur, the headache now becomes “transformed” into a more chronic, often daily, pattern. Chronic analgesic overdose appears to deplete serotonin in the central nervous system, and there is also evidence that it results in damage to receptor sites. As a consequence, analgesic medication taken daily will actually perpetuate the headache cycle. The patient is in a “catch-22” situation because discontinuing the medication abruptly results in a severe “rebound” headache which is resistant to both prophylactic or acute migraine therapy.

2. Increasing frequency of headaches

When headaches become more frequent, an underlying provocative mechanism may be present and should be sought—and if possible, rectified. If lifestyle readjustment or acute treatment cannot rectify the situation, prophylactic medication may be indicated. In most cases, prophylaxis should be continued for some months after which it can be slowly decreased until it is no longer needed.

3. Emergence of a concomitant comorbid disorder.

Studies have shown that migraine is often accompanied by other serotonergic disorders such as peripheral vascular disease, seizures, or depression. When such a condition coexists, its ideal treatment would be an agent that acts as a migraine prophylactic. For example, a migraineur with depression might be appropriately treated with a tricyclic antidepressant or a selective serotonin reuptake inhibitor (SSRI). A patient with peripheral vascular disease might do well with a calcium channel blocker. If hypertension coexists, a beta blocker would be an appropriate agent, serving to help control the hypertension as well as acting as prophylaxis for the patient’s migraine.

4. Failure of acute therapy

The inability to control acute migraine attacks is another indication for the use of prophylactic medication. These patients may require frequent rescue medications.

The definition of successful prophylaxis does not imply that migraine will no longer occur. Successful prophylaxis is usually considered that which will decrease the frequency of attacks by 50% or more. If that goal is reached, a decision should be made whether it is worth the cost and the risk of adverse effects to maintain the prophylactic program. If the decision is made to continue, the agent should be continued for four to six months after which its dosage is gradually decreased and the patient re-evaluated.

The Choice of a Prophylactic Agent

The physician has a wide variety of agents from which to select the most appropriate prophylactic therapy for a given patient, although only four (propranolol, timolol, methysergide maleate, and divalproex sodium) are currently recognized as effective for the indication. As previously indicated, the presence of a comorbid condition will often direct the physician to that agent which will treat that condition while at the same time act as a preventative against acute migraine attacks. Because precise dosing regimens for migraine prophylaxis are not available for the majority of the drugs, the prescribing physician is well-advised to use those drugs with which he/she is familiar, to start with a low dose, and to increase the dosage slowly as indicated. Treatment should be maintained at an effective level or discontinued in the face of an adverse event or when therapeutic success is not achieved at dosages approved for other indications of the drug.

In general, migraine prophylactics can be divided into several categories based on their biochemical mode of action:

Treatment of the Acute Migraine Attack

Most migraineurs are capable of recognizing the prodrome phase, the earliest phase of the migrainous process, and of predicting the onset of a full-blown attack. At this time acetaminophen, Excedrin®, aspirin, and other non-steroidal anti-inflammatory drugs (NSAIDs), are often therapeutically effective. The aura phase, if present, provides an opportune time to initiate therapy in anticipation of the headache phase.

The ergot preparations

Prior to the introduction of the triptan group of therapeutic agents, the pharmaceutical treatment of the acute migraine attack was dominated by the ergot group of drugs and they still command considerable popularity. Ergotamine tartrate is available in a variety of forms, either alone or in combination with caffeine. Most are administered orally, but intranasal, sublingual, rectal, and parenteral forms are also available and are particularly useful in the migraine patient who suffers from nausea and vomiting during an acute attack.

The most commonly used ergotamine preparations include:

1. Cafergot®, (caffeine plus ergotamine tartrate, Novartis)

2. Wigraine® (caffeine plus ergotamine tartrate, Organon)

3. D.H.E. 45® (dihydroergotamine tartrate parenteral, Novartis)

4. Ergomar® (ergotamine tartrate, Lotus)

In the late 1960s and early 1970s, it became apparent to researchers in the field of migraine that serotonin (5-hydroxytryptamine, 5-HT) and its receptors played a significant role in the pathogenesis of migraine. Although the use of ergotamine for the treatment of acute migraine was initially prompted by its vasoconstrictive activity which countered the cerebral vasodilatation present in migraine, it now became likely that the anti-migraine properties of ergot were attributable to a non-selective serotonin receptor agonist activity. However, the vasoconstrictive properties of ergotamine do exist and pose a threat to patients with coronary, cerebral, or peripheral arterial insufficiency. Because of this, these preparations should not be used in anyone with known or suspected problems of vascular insufficiency.

The “new generation” of 5HT receptor agonists, the triptans, made their appearance in 1991 with the European launching of sumatriptan (Imirex/Imigran®, Glaxo Wellcome). Sumatriptan, available in oral, intranasal, and subcutaneous form, is a selective 5HT-1 agonist and has been found highly effective in the treatment of the acute migraine attack. It also has a good safety profile. It was approved for subcutaneous use in the United States in 1993 and for oral use in the United States in 1995.

In 1996, concerns about monopoly on the part of the FDA compelled Glaxo to sell its second triptan derivative, zolmitriptan to Astra/Zeneca Pharmaceuticals and it is currently marketed as Zolmig®. This created a unique marketing situation where Glaxo found itself competing sumatriptan against its own former product, zolmitriptan. Astra/Zeneca was forced to repeat clinical studies on zolmitriptan already performed and completed by Glaxo. The picture was further complicated by the release of another compound by Glaxo called rizatriptan (Amerge®). More recently, naratriptan (Maxalt®, Merck) has been approved for marketing. Thus, the physician currently has available four triptan products for treatment of the acute migraine attack – sumatriptan and rizatriptan (Imitrex® and Amerge®, Glaxo-Wellcome), zolmitriptan (Zomig®, Astra/Zeneca), and rizatriptan (Maxalt®, Merck). Additional triptans and related compounds are in the process of development.

All four of the triptans are currently approved for safety and efficacy. They are well tolerated with relatively few adverse effects, most of which are of minor clinical significance. Rare cases of exacerbations of coronary artery heart disease have been reported and caution is necessary in that group of patients. All four preparations report a response rate of 60% to 70% occurring within a few hours post-medication. (As might be expected, claims of superiority over the other triptans have been reported by all drug sponsors. For example, rizatriptan has been reported to relieve migraine headache faster and to control migraine-associated symptoms more effectively than sumatriptan. Similar claims have been made for zolmitriptan. At the present time further studies, especially involving dose-ranging, are ongoing.)

Rescue therapy

If treatment is ineffectual during the headache phase of the migraine attack, it may be necessary to resort to “rescue” therapy. A combination of drugs or a dopamine antagonist such as a phenothiazine may be used. As a last resort, a narcotic, such as butorphanol (Stadol®), may be necessary.

None of the above therapies “cure” migraine. It remains a chronic problem subject to recurrences. However, spontaneous remissions decrease after the age of 50 and many migraineurs are eventually asymptomatic. Sequelae to migraine are rare. A recent study reported that migraine in women of child-bearing age was associated with an increased risk of ischemic, but not hemorrhagic, stroke. Oral contraceptives, smoking, and hypertension appeared to increase the risk. The authors estimated that 20% to 40% of strokes in women are associated with migraine.

Conclusion

The management of a migraine patient is often challenging. The variability in migraine manifestations that exists between patients requires individual management. In addition, in a manner similar to the diabetic patient, the migraineur requires significant self-management, a factor which may be difficult to reconcile with the physician’s role. Better understanding of the migraine process and the development of new and useful therapeutic tools should help tremendously.